Introduction

Tryptophan hydroxylase inhibitor.13

Uses for Telotristat Etiprate

Carcinoid Syndrome Diarrhea

Used (in combination with somatostatin analog therapy) for treatment of carcinoid syndrome diarrhea inadequately controlled by somatostatin analog therapy alone127 (designated an orphan drug by FDA for the treatment of carcinoid syndrome in patients with neuroendocrine tumors).6

Carcinoid syndrome, a condition associated with serotonin overproduction, is characterized by flushing, diarrhea, wheezing, occasionally congestive heart failure, and various other manifestations.135 Although somatostatin analogs (e.g., octreotide, lanreotide) are standard treatment for carcinoid syndrome and are effective initially in most patients, some patients may not respond adequately or may develop recurrent symptoms, including diarrhea, despite therapy.2

Because the integrity of the GI tract wall may be impaired in patients with metastatic carcinoid tumors, monitor patients for development of constipation and/or severe persistent or worsening abdominal pain.1 If such manifestations occur, discontinue therapy.1

Lactation

Not known whether telotristat ethyl distributes into human milk.1 Effects of the drug on nursing infants and on milk production also not known.1 In addition, effects of local GI and systemic exposure to the drug in breast-fed infants are unknown.1

Consider benefits of breast-feeding to the infant along with the women's clinical need for the drug and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1 Monitor breast-fed infants for symptoms of constipation.1 (See Constipation under Cautions.)

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy observed in patients ≥65 years of age compared with younger adults, but increased sensitivity cannot be ruled out.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Mild hepatic impairment does not alter pharmacokinetics of telotristat.1 Not studied in patients with moderate or severe hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Interactions for Telotristat Etiprate

Metabolized by carboxylesterases to telotristat.1 Telotristat further metabolized by decarboxylation and deamination, including to a major inactive metabolite; however, drug interaction potential of this metabolite unknown.13

Neither telotristat ethyl nor telotristat is a substrate of CYP isoenzymes in vitro.1 Telotristat ethyl and telotristat not adequately studied in vitro to indicate whether the drug or its active metabolite inhibit CYP isoenzymes 2B6, 2C8, or 2C9 or induce CYP isoenzymes 1A2 or 2B6.1 Effects on CYP3A4 not fully established.3 (See Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

In vitro, telotristat ethyl inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 In vitro, telotristat is not an inhibitor of P-gp and BCRP, but is a substrate of P-gp at clinically relevant concentrations.13

Telotristat Etiprate Pharmacokinetics

Absorption

Bioavailability

Telotristat ethyl is a prodrug that is converted in vivo to telotristat; peak plasma concentrations and AUC of telotristat ethyl and telotristat attained within 0.5–2 hours and 1–3 hours, respectively, after a single oral dose of telotristat etiprate.1

Following a single oral dose (dosage range: 100 mg to 1 g), peak plasma concentrations and AUC of telotristat ethyl and telotristat appear to be dose proportional under fasted conditions.1

Following multiple-dose administration of telotristat ethyl 500 mg 3 times daily, negligible accumulation at steady state for both telotristat ethyl and telotristat.1

Plasma concentrations of telotristat ethyl and telotristat decline in a biphasic manner.1

Food

Administration of telotristat ethyl 500 mg with a high-fat meal increased peak concentrations of telotristat ethyl and telotristat by 112 and 47%, respectively, and increased AUC0–inf of telotristat ethyl and telotristat by 264 and 33%, respectively.1

Special Populations

Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration): Not studied; effect on pharmacokinetics not known.1

Renal impairment: In patients with mild to moderate renal impairment (Clcr 20–89 mL/minute), pharmacokinetics similar to those in patients with normal renal function.1 Not studied in patients with end-stage renal disease who require dialysis.1

Age (18–83 years), gender, and body weight (40–115 kg) do not have clinically important effects on pharmacokinetics of telotristat.13

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

Telotristat ethyl and telotristat: >99%.1

Elimination

Metabolism

Telotristat ethyl is hydrolyzed to telotristat (active metabolite), principally by carboxylesterases in non-CYP-dependent pathways.13 Further metabolized to a major inactive metabolite (LP-951757).13

Elimination Route

Telotristat ethyl is eliminated in feces (92.8%) and urine (<0.4%).1

Half-life

Telotristat ethyl: Approximately 0.6 hours.1

Telotristat: Approximately 5 hours.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

Telotristat ethyl is a prodrug of telotristat, a tryptophan hydroxylase inhibitor.13

Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin from tryptophan in the GI tract.1234

Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the GI tract.1 In carcinoid syndrome, a condition associated with overproduction of serotonin, inhibition of tryptophan hydroxylase activity by telotristat and telotristat ethyl reduces peripheral serotonin production and frequency of carcinoid syndrome diarrhea.1

Telotristat is 29-fold more potent than telotristat ethyl in its inhibition of tryptophan hydroxylase in vitro.1

Advice to Patients

Risk of constipation, which may be severe.1 Advise patients to discontinue telotristat ethyl and contact their clinician if severe constipation or severe persistent or worsening abdominal pain occurs.1

Importance of taking telotristat ethyl tablets with food.1

When short-acting octreotide is used in combination with telotristat ethyl, importance of administering short-acting octreotide acetate ≥30 minutes after administration of telotristat ethyl.1

If a dose is missed or vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.